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Cited by 711Ion Transport and Channel RegulationIon channel regulation and functionUbiquitin and proteasome pathways

Phosphorylation of Nedd4‐2 by Sgk1 regulates epithelial Na+ channel cell surface expression

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Debonneville, Christophe, Flores, Sandra Y., Kamynina, Elena, Plant, Pamela J., Tauxe, Caroline, Thomas, Marc A., Münster, Carole, Chraïbi, Ahmed +5 more·2001·The EMBO Journal
DOI 10.1093/emboj/20.24.7052PMC PMC125341
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Abstract

The epithelial Na(+) channel (ENaC) plays an essential role in the regulation of whole body Na(+) balance and blood pressure. The cell surface expression of this channel, a complex of three subunits (alpha, beta and gamma ENaC), has been shown to be regulated by hormones such as aldosterone and vasopressin and by intracellular signaling, including ubiquitylation and/or phosphorylation. However, the molecular mechanisms involving phosphorylation in the regulation of ENaC are unclear. Here we show by expression studies in Xenopus laevis oocytes that the aldosterone-induced Sgk1 kinase interacts with the ubiquitin protein ligase Nedd4-2 in a PY motif-dependent manner and phosphorylates Nedd4-2 on Ser444 and, to a lesser extent, Ser338. Such phosphorylation reduces the interaction between Nedd4-2 and ENaC, leading to elevated ENaC cell surface expression. These data show that phosphorylation of an enzyme involved in the ubiquitylation cascade (Nedd4-2) controls cell surface density of ENaC and propose a paradigm for the control of ion channels. Moreover, they suggest a novel and complete signaling cascade for aldosterone-dependent regulation of ENaC.

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Cited by

Sorted by citations

Authors
Debonneville, C., Flores, S. Y., Kamynina, E., Plant, P. J., Tauxe, C., Thomas, M. A., Münster, C., Chraïbi, A., Pratt, J. H., Horisberger, J., Pearce, D., Loffing, J., & Staub, O.
Affiliations
  • University of Zurich (CH)
  • University of Lausanne (CH)
  • Indiana University Indianapolis (US)
  • University of San Francisco (US)
Corresponding author
Staub, Olivier
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2001-12-17
Volume
20
Issue
24
Pages
7052-7059
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1093/emboj/20.24.7052
PMC
PMC125341
OpenAlex
W2136901254
Cited by
711
References
0
Citations by year
2026: 17 · 2025: 12 · 2024: 7 · 2023: 17 · 2022: 24 · 2021: 17 · 2020: 19 · 2019: 30 · 2018: 20 · 2017: 14 · 2016: 18 · 2015: 20 · 2014: 25 · 2013: 30 · 2012: 35
FWCI
13.92
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
epithelial Na+ channel, Nedd4-2, phosphorylation, cell surface expression, aldosterone signaling, ubiquitin ligase, PY motif, ion channel modulation, sodium balance
MeSH terms
Nedd4 Ubiquitin Protein Ligases, Serum-Glucocorticoid Regulated Kinases, Amino Acid Sequence, Animals, Calcium-Binding Proteins, Cell Line, Ligases, Nuclear Proteins, Oocytes, Phosphorylation, Protein Binding, Xenopus laevis, Sodium Channels, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Ubiquitin, Xenopus Proteins, Ubiquitin-Protein Ligases, Epithelial Sodium Channels, Endosomal Sorting Complexes Required for Transport

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